This invention was supported in part by Grant GM-07874 from the National Institutes of Health.
This invention relates to a process for the conversion of azetidine carboxylic acids into corresponding beta-lactams, to intermediates useful in the synthesis of biologically active beta-lactams and to methods for the synthesis thereof.
Beta-lactams have received increasing study as an essential component in several families of compounds having useful biological, especially antibacterial, activity, e.g. the beta-lactam-thiazolidine ring (penam) system common to all penicillins and the beta-lactam-dihydrothiazine (cepham) nucleus common to the cephalosporins, and increasingly in monocyclic beta-lactams which have been recently described. For example, Hashimoto et al. in J.A.C.S. 98(10): 3023 (May 12, 1976), have described the structure of nocardicin, a monocyclic beta-lactam having antibacterial activity. A number of additional monocyclic beta-lactams, many of which are structurally similar to the bicyclic pencillins and cephalosporins, have been described in Belgium Pat. No. 830,934 and by Bose et al. in J.Med.Chem. 17(4): 541 (1974).
At present, most monocyclic beta-lactams are synthesized by the reaction devised by A. K. Bose wherein azidoacetyl chloride is reacted with a Schiff base to form the beta-lactam. While in general a satisfactory technique, the azidoacetyl chloride reagent is relatively expensive and dangerous to work with in large quantities due to the risk of explosions.
Accordingly, particularly in view of the increasing research being directed to the preparation of biologically active beta-lactams and the use of beta-lactam intermediates in the synthesis of valuable antibacterial compounds such as the penicillins, cephalosporins, nocardicins, etc., there is need for a safe and inexpensive method for the preparation of beta-lactams and related intermediates.
The aforementioned copending U.S. Patent application Ser. No. 736,343 describes a low temperature dianion oxygenation process first reported by Wasserman and Lipshutz in Tetrahedron Letters: 4613 (1976) for the preparation of beta-lactams from azetidine-2-carboxylic acid starting materials. The present invention provides an even more convenient, alternative procedure for accomplishing the same conversion, employing the reactivity of iminium salts toward nucleophiles, e.g. see R. T. Dean et al. in J.A.C.S. 98: 7448 (1976), the contents of which are incorporated by reference herein. The present invention is furthermore applicable to lactam formation in the presence of active (e.g. benzylic) hydrogen atoms in the substituent attached to the lactam ring nitrogen atom, which is not feasible in the previous low temperature dianion oxygenation process.